The eukaryotic translation initiation factor eIF4E is elevated in about 30% of cancers. eIF4E promotes proliferation and survival by the coordinated upregulation of the expression of genes involved in these pathways. eIF4E functions in both the nucleus and cytoplasm. In the cytoplasm, it binds the 7-methyl guanosine (m7G) cap found on the 5'end of mRNAs thereby allowing translation initiation. Importantly, up to 68% of eIF4E is found in the nucleus, where it promotes mRNA export of a subset of transcripts coding for proteins involved in survival and proliferation. This mRNA export activity contributes substantially to its oncogenicity. eIF4E must bind the m7G cap to act in translation, export and transformation. We found that inhibition of eIF4E function by introduction of a physical mimic of the m7G cap, ribavirin, leads to inhibition of eIF4E's survival and proliferative activities, and is associated with clinical benefit in leukemia patients. Although eIF4E's role in translation is well understood, its molecular role in mRNA export is not. Our studies revealed that eIF4E dependent mRNA export is distinct from bulk mRNA export, being CRM1 dependent. We will examine the extent to which eIF4E dependent mRNA export uses the CRM1 export machinery. Further, we identified a 50-nucleotide element in the untranslated region of target mRNAs referred to as an eIF4E sensitivity element (4E-SE). The 4E-SE imparts sensitivity to eIF4E (allowing preferential export). In subsequent studies we identified a factor, the leucine-rich pentatricopeptide repeat protein LRP, which directly binds the 4E-SE element. We will examine the role LRP plays in this export process. Finally, we will examine the impact on eIF4E activity of a novel partner, the inhibitor of invasion protein IIp45. IIp45 appears to impair eIF4E function in a new manner. We propose three specific aims to investigate these possibilities: 1. Determine the molecular mechanism of eIF4E dependent mRNA export, 2. Define the role that LRP plays in this pathway and 3. Examine novel modes of control of eIF4E by the IIp45 protein. We believe that elucidation of the molecular underpinnings of eIF4E dependent mRNA export will yield new insights into the mechanics of eIF4E-mediated transformation. Further, these findings could provide the basis for novel therapeutic strategies for cancers characterized by dysregulated eIF4E. PUBLIC HEALTH RELEVANCE: The eukaryotic translation initiation factor eIF4E is dysregulated in many human cancers including cancers of the breast, head &neck, colon, prostate and blood. Our project is designed to understand the mechanisms and therapeutic implications of this dysregulation.